System for release in lower gastrointestinal tract

ABSTRACT

A system whereby a substance which is orally taken and to be delivered into the lower digestive tract is selectively delivered into the lower digestive tract. More particularly, a system which makes it possible to surely and quickly deliver the aimed substance to the lower digestive tract without being affected by pH change in the digestive tract due to change in bacterial flora. Compositions disintegrating in the lower digestive tract characterized by containing a compound &lt;A&gt;, which has a molecular weight of 1000 or less and has a disulfide bond, and a polymer &lt;B&gt;, which has a molecular weight exceeding 1000 and is digested by enteric bacteria and/or undergoes softening, swelling or dissolution due to a decrease in pH; molded products with the use of these compositions; and preparations with the use of these molded products.

TECHNICAL FIELD

The present invention relates to a system that orally uptakes a materialdesired to be delivered to a lower part of the gastrointestinal tractand delivers it selectively to the lower part of gastrointestinal tract.More specifically, the present invention relates to a system thatunfailingly and quickly delivers an objective material selectively to alower part of gastrointestinal tract without being influenced by achange in pH in the gastrointestinal tract due to a variation in thebacterial flora. Also, the present invention relates to a compositionthat disintegrates at a lower part of gastrointestinal tract, comprisinga compound <A> having a molecular weight of 1,000 or less and having adisulfide bond and a polymer <B> having a molecular weight of above1,000 and having a property of being decomposed by enterobacteria,and/or a property of being softened, swelled or dissolved due to adecrease in pH, to a formed product comprising such a composition, andto a preparation comprising such a formed product.

BACKGROUND ART

To deliver a drug specifically to a colon in the gastrointestinal tractresults in an increased therapeutic effect by local accumulation of thedrug upon the treatment of local gastrointestinal tract diseases such asulcerative colitis and clonal diseases. In such a delivery, because noabsorption of the drug occurs before it reaches the colon, side effectsattributable to systemic circulation of the drug is decreased and theloss of the drug before it reaches the site where it is effective can beprevented.

Expecting these, many reports have been made on the system that deliversa drug targeting the colon and are roughly classified into the followingthree groups.

A first group includes a system that releases a drug in response to achange in pH. In the case of a general enteric-coated preparation onwhich many reports have been made, due to a large biogenic influence ofa change in pH in a day in the gastrointestinal tract or of diets, itmay occur that the preparation is disintegrated in an upper part ofsmall intestine or on the contrary it is dejected as it is without beingdisintegrated. Therefore, it cannot be said that colon-specific deliveryof a drug is unfailingly realized. Furthermore, a system in which anenteric coating is applied outside acid-soluble coating that is designedto utilize a decrease in pH due to an organic acid produced in the colonis disclosed (JP 10-152431A). However, since disintegration in responseto a slight change in pH is required, the system is susceptible to theinfluence of a change in bacteria flora and the like in the colon and itis difficult to unfailingly deliver a drug colon-specifically.

A second group includes a system that releases a drug time-dependently(JP 7-72130B, JP 7-196477A, EP 0384646B, and JP 7-2650A and 7-10745A).The release sites of them are controlled by time of migration of thepreparation in the gastrointestinal tract, so that the release of thedrug is greatly susceptible to the biogenic influences of the movementof gastrointestinal tract, of diets or of pathological state.Accordingly, problems arise. In the case where the residence time in thesmall intestine of the preparation is long, it is disintegrated in thesmall intestine. In the case where the residence time in the smallintestine and large intestine of the preparation is short, it isdejected as it is without being disintegrated. Therefore, it isdifficult to unfailingly deliver a drug in a specified region of a lowerpart of gastrointestinal tract.

A third group includes systems that utilize enterobacteria on which anincreasing number of studies have been made in recent years. Thesesystems are roughly classified into two systems. One is a system inwhich the preparation contains an azo polymer or a disulfide polymer,which is decomposed and disintegrated by the reducing activity ofenterobacteria (J. Kopecek et al., Pharmaceutical Research, Vol. 9, No.12, pages 1540-1545, 1992; Y. Kimura, et al., POLYMER, Vol. 33, No. 24,pages 5294-5299, 1992; and WO91/11175). Another is a system in which thepreparation contains a polysaccharide, which is decomposed anddisintegrated by the polysaccharide decomposing activity of mainlyanaerobic bacteria in the intestine (JP 5-508631A; W. G. Cook, et al.,Pharmaceutical Research, Vol. 10, No. 10, S223, 1993).

Reportedly, the reducing activity of the enterobacteria is high, differsonly slightly between the species of bacteria, and less influenced by achange in bacterial flora due to a disease or the like (T. Mitsuoka:Metabolism of Enteric Flora, pages 1-17, Academic Printing Center(1988)). However, in the system using an azo polymer or a disulfidepolymer thus far disclosed, the decomposition rate of the polymer is low(J. Kopecek, et al., Pharmaceutical Research, Vol. 9, No. 12, pages1540-1545, 1992). Especially in the case of azo polymer, there is aconcern about production of noxious substances derived from the azobond, so that the problem arises that the system cannot endure along-term use also in consideration of safety.

The system using a polysaccharide may be considered to have a lesssevere problem on safety since it uses a substance that has originallybeen used as dietary fiber. Generally, these substances have theproblems. They are decomposed in the colon at low decomposition rates(W. G. Cook, et al., Pharmaceutical Research, Vol. 10, No. 10, S223,1993). In a state of a disease, their disintegration does not proceeddue to a change in enterobacteria flora, especially a decrease inanaerobic bacteria, which are main bacteria that decomposepolysaccharides (T. Mitsuoka: Metabolism of Enteric Flora, pages 1-17,Academic Printing Center (1988)).

An example of the system using a polysaccharide is one that useschitosan. Chitosan, which is a kind of polysaccharide, undergoesdecomposition by enterobacteria and is softened or dissolved as a resultof a decrease in pH in the colon. Therefore, it is frequently used in adrug delivery system targeting the colon (JP 4-41422A and 4-247026A).However, the activity of enzymes such as chitosanase and lysozyme thatdecompose chitosan is insufficient in the colon and rather it isconsidered that the mechanism of disintegration of chitosan systemdepends on a decrease in pH in the colon. Therefore, the problem arisesthat the function of the system is strongly influenced by the colonic pHvariation in the biogenic condition or the change of enterobacteriaflora in a state of disease.

Furthermore, there has been proposed a system called CODES intended toachieve colon-specific drug delivery that avoids the influence of pHvariation in the colon and releases the drug in the colon is not bymeans of time control (WO95/28963). This is a system that containstherein a saccharide that will be metabolized into an organic acid byusing enterobacteria in the colon and that is coated with anacid-soluble film that is dissolved with the organic acid. However, thissystem is also questionable as to whether or not it enables unfailingcolon-specific drug delivery.

Therefore, a colon-specific, unfailing and quick drug delivery systemthat is not influenced by a change or difference in pH in the colonbetween individuals, uptake of diets or the like or a change ofenterobacteria flora has been desired.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a system for deliveringan objective material selectively to a lower part of gastrointestinaltract, unfailingly and quickly without being influenced by a pHvariation or a change of enterobacteria flora. Also, an object of thepresent invention is to provide a composition for disintegration inlower gastrointestinal tract, a formed product comprising such acomposition, and a preparation comprising such a formed product. Moreparticularly, an object of the present invention is to provide a systemthat orally uptakes a material desired to be delivered to a lower partof the gastrointestinal tract and delivers it selectively to the lowerpart of gastrointestinal tract. The system has dissolved theabove-mentioned problems encountered in the prior art, more specificallythe problems of being susceptible to the influences by various factorsoriginating in the biogenic condition, such as a pH variation, a changein enterobacteria flora, or movement of gastrointestinal tract andinfluence of uptake of diets. Also, an object of the present inventionis to provide a composition for disintegration in lower gastrointestinaltract, a formed product comprising such a composition, and a preparationcomprising such a formed product. An object of the present invention isto provide a capsule, a film, a sheet or a coating film and so forth asthe formed product.

The present inventors have made extensive studies in order to achievethe above-described objects. As a result, they have found that acomposition for disintegration in lower gastrointestinal tract,comprising a compound <A> having a molecular weight of 1,000 or less andhaving a disulfide bond (hereinafter, abbreviated as “compound <A>”) anda polymer <B> having a molecular weight of above 1,000 and having aproperty of being decomposed by enterobacteria, and/or a property ofbeing softened, swelled or dissolved due to a decrease in pH(hereinafter, abbreviated as “polymer <B>”) quickly disintegrates in afilm disintegration test conducted in a pseudo-enteral environment andthat the composition disintegrates selectively at a lower part of thegastrointestinal tract in an animal experiment. The present inventionhas been completed based on the discovery.

Hereinafter, the present invention will be illustrated.

A first aspect of the present invention provides a composition fordisintegration in lower gastrointestinal tract, characterized bycontaining a compound <A> and a polymer <B>.

A second aspect of the present invention provides a composition forrelease in lower gastrointestinal tract, characterized in that a domaincontaining a compound <A> is dispersed in a matrix containing a polymer<B>.

A third aspect of the present invention provides a composition fordisintegration in lower gastrointestinal tract, characterized bycontaining a compound <A>, a polymer <B>, and a substance that controlsdisintegration rate in lower gastrointestinal tract.

A fourth aspect of the present invention provides a formed product forreleasing an active ingredient <C> in lower gastrointestinal tract,comprising a shaped product of the composition for disintegration inlower gastrointestinal tract, characterized by containing a compound <A>and a polymer <B>.

A fifth aspect of the present invention provides a preparation forrelease in lower gastrointestinal tract, characterized in that acomposition for release in lower gastrointestinal tract characterized bycontaining at least an active ingredient <C>, a compound <A>, and apolymer <B> is coated with an enteric polymer film.

A sixth aspect of the present invention provides a preparation forrelease in lower gastrointestinal tract, characterized in that acomposition containing an active ingredient <C> and a pharmaceuticallyacceptable carrier is coated with a composition for disintegration inlower gastrointestinal tract characterized by containing a compound <A>and a polymer <B> and further coated with an enteric polymer film.

A seventh aspect of the present invention provides a system for peroraluptake of a material desired to be delivered to lower gastrointestinaltract and selective release in the lower gastrointestinal tract,characterized in that a composition for disintegration in lowergastrointestinal tract characterized by containing a compound <A> and apolymer <B> and an enteric polymer film are used.

An eighth aspect of the present invention provides a system for peroraluptake of a material desired to be delivered to lower gastrointestinaltract and selective release in the lower gastrointestinal tract,characterized in that the material desired to be delivered to the lowergastrointestinal tract is coated with or added to a composition fordisintegration in the lower gastrointestinal tract characterized bycontaining a compound <A> and a polymer <B>, and further coated with anenteric polymer film.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph substituting a drawing, showing a surface of afilm obtained as a result of Example 1, with (a) showing the statebefore the test and (b) showing results obtained by use of carbonatebuffer.

FIG. 2 is a photograph substituting a drawing, showing a surface of afilm obtained as a result of Example 1, illustrating results with asuspension of cecum contents.

FIG. 3 is a photograph substituting a drawing, showing a surface of afilm obtained as a result of Comparative Example 1, with (a) showing thestate before the test and (b) showing results obtained by use ofcarbonate buffer.

FIG. 4 is a photograph substituting a drawing, showing a surface of afilm obtained as a result of Comparative Example 1, illustrating resultswith a suspension of cecum contents.

FIG. 5 is a diagram illustrating the chronological state of the seamlesscapsules in gastrointestinal tract with lapse of time afteradministration of seamless capsules to a rat (n=3) with fed condition.

FIG. 6 is a photograph taken by use of a digital microscope, showingresults of disintegration tests of the cast film prepared in Example 5and the cast film of comparative composition. (a) represents the castfilm prepared in Example 5 and (b) represents the cast film prepared inComparative Example 2. In each photograph, left-hand side (film lookingwhite) indicates results of shaking in carbonate buffer and right handside indicates results of shaking in the suspension of cecum contents.

FIG. 7 is a diagram illustrating chronological blood levels of a modeldrug and a marker drug after administration of the coated capsules inExample 6 to a dog.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be illustrated in detail.

First, each component element and terms referred to herein will beexplained.

The term “lower gastrointestinal tract” as used herein means ileum andlarge intestine parts. The term “ileum” refers to a third part of smallintestine that continues to duodenum and jejunum. The term “largeintestine” means a site toward the site consisting of cecum, colon andrectum. The term “cecum” refers to a blind sack (cul-de-sac) startingfrom the large intestine and in one end of which the ileum opens. In thelower gastrointestinal tract, enterobacteria increase from the ileum andin the large intestine they inhabit in many kinds and in large numbers.

The term “composition for disintegration in lower gastrointestinaltract” as used herein refers to a functional material that disintegratesselectively in the lower gastrointestinal tract. The “composition fordisintegration in lower gastrointestinal tract” of the present inventionis characterized by containing a compound <A> and a polymer <B>. It mayfurther contain a substance that controls its disintegrability in thelower gastrointestinal tract. The substance that controls thedisintegration rate may be divided into a substance that impartsresistance to disintegration in the small intestine and a substance thataccelerates disintegration in the lower gastrointestinal tract.

The “composition for disintegration in lower gastrointestinal tract” ofthe present invention may be a composition in which the compound <A> andthe polymer <B> are mixed uniformly, a composition in which they arecontained in a specified order, or a composition in which they arecontained completely in disorder and non-uniformly. However, acomposition in which the domain that contains the compound <A> isdispersed in a matrix that contains the polymer <B> is preferred. Morespecifically, a composition in which the particles that contain thecompound <A> are uniformly dispersed in a matrix that contains thepolymer <B> and is mainly composed of the polymer <B>. The particlesthat contain the compound <A> are desirably those that are sufficientlysmall as compared with the film thickness when they are formulated intothe “composition for disintegration in lower gastrointestinal tract” andthat have narrow particle size distribution.

The term “matrix” as used herein indicates the state where the polymerexists alone or in admixture, integrated into a uniform mixture orcomposition. The term “domain” refers to the state where a componentincompatible with a matrix is dispersed and almost uniformly located inthe matrix. The matrix that has domains has different properties fromthose of simple mixture or simple composition composed of the samecomponents.

The matrix may contain a substance that controls disintegration in lowergastrointestinal tract.

The “compound <A> having a molecular weight of 1,000 or less and havinga disulfide bond” used in the present invention has the property that itis decomposed into lower molecular compounds as a result of cleavage ofthe disulfide bonds due to reduction by enterobacteria so thatimprovement of water-solubility and/or acidity of the decompositionproducts is higher than the compound <A>. Such an improvement inwater-solubility means that when the composition contains water orcontacts water, the particles that contain the compound <A> aredissolved as a result of reduction reaction by enterobacteria. This inturn contributes to formation of micro holes in the film. Thisaccelerates penetration of water in the lumina into the composition ofthe present invention or causes the enterobacteria to sufficientlypenetrate into the composition of the present invention. As a result,the disintegrability of the composition can be increased. On the otherhand, an increase in acidity contributes to softening, swelling ordissolution of the specified polymer provided in the present invention.Increased acidity and increased water-solubility simultaneously impartedsynergistically contribute to disintegration of film in lowergastrointestinal tract.

The compound <A> includes an oligo peptide that is an amino acidderivative having a disulfide bond, to which cysteine or a peptidecontaining cysteine is bonded through the disulfide bonds. The compound<A> includes not only naturally deriving ones but also those peptidesthat can be synthesized from D-form or L-form amino acids. Specificexamples of the compound <A> include L-cystine, D-cystine, DL-cystine,diglycyl cystine, cystamine, L-cystinyldiglycine, glutathione disulfideand so forth as the amino acid derivative having a disulfide bond, andthioglycolic acid disulfide (HOOC—R—S—S—COOH/R represents a loweralkylene group) as a synthetic organic low molecule. Cystines(L-cystine, D-cystine, DL-cystine, or any optional mixtures thereof) aremore preferable.

The addition amount of the compound <A> is not particularly limited sofar as no problem occurs in forming preparations. More specifically, thecompound <A> may be contained in the composition of the presentinvention in a ratio of 1 to 90%. It may be contained in the system ofthe present invention in a ratio of 1 to 90%. In the formed product ofthe present invention, it may be contained in a ratio of 1 to 90%. Inthe case where it is used in the coating film, it is preferred that itbe used in a ratio of 10 to 80% in the coating film. The “%” as usedherein refers to % of weight per weight and values each based on dryweight.

In the case where it is used in the composition, more particularlyformed product or coating film of the present invention, the compound<A> is preferably dispersed in a base material in the state ofparticles. The reduction by the enterobacteria causes the disulfidebonds to be cleaved and as a result, the compound <A> is decomposed intolower molecular weight compounds to increase the water-solubility of thedecomposition products. Upon contact with moisture, a large number ofmicro holes are formed on the portion where the compound <A> existed inthe form of particles. This accelerates penetration of water in thelumina into the composition of the present invention or theenterobacteria sufficiently penetrate into the composition. Therefore,the disintegrability of the composition can be further increased.

The “polymer <B> having a molecular weight of above 1,000 and having aproperty of being decomposed by enterobacteria, and/or a property ofbeing softened, swelled or dissolved due to a decrease in pH” means apolymer having a molecular weight of above 1,000, having the property ofbeing decomposed by protease, lysozyme and polysaccharidases and soforth of the enterobacteria, having the property of being softened,swelled or dissolved by a decrease in pH, that is, lowering of pH fromthe vicinity of neutrality to increase acidity, or having the bothproperties. Simultaneous occurrence of the decomposition by theenterobacteria and softening, swelling or dissolution due to a decreasein pH, the disintegration of the composition containing the polymer <B>,more particularly, coating film in lower gastrointestinal tract proceedsfurther, so that the material desired to be delivered to the lowergastrointestinal tract can be released more quickly andsite-selectively. Therefore, the polymer <B> is preferably a polymerhaving the property of being decomposed by the enterobacteria and havingthe property of being softened, swelled or dissolved by a decrease inpH. The molecular weight as used herein refers to an average value,which may be either a number average value or a weight average value.

The polymer <B> can be roughly classified into two groups, i.e., anatural cationic polymer such as chitosan and a synthetic cationicpolymer such as acrylic acid-based cationic polymer. Specific examplesof the polymer <B> include chitosan as the natural cationic polymer anddimethylaminoethyl methacrylate/methyl methacrylate/butyl methacrylatecopolymer (for example, trade name: Eudragit E(Rhoem GmbH, Germany)),polyvinyl acetal diethylaminoacetate (for example, trade name: AEA(Sankyo Company, Limited) and so forth as the synthetic cationicpolymer. Natural cationic polymer is preferred, more preferably chitosanmay be mentioned.

As the polymer <B>, two or more of the above mentioned polymers may beused in admixture. In this case, a combination of a natural cationicpolymer and a synthetic cationic polymer is preferable. Combination ofdifferent kinds of polymer can improve the function of the polymer <B>,such as imparting water resistance or controlling disintegration rate.For example, the water resistance can be improved by combining ahydrophobic polymer that is acid soluble and difficult to swell withwater as the synthetic cationic polymer.

Chitosan is a deacetylated compound that is obtained by treating chitincontained in large amounts in crustaceans such as crab and lobster withusually a concentrated alkali and completely or partially deacetylatingthe acetyl groups. It has a linear polysaccharide structure composed of2-amino-2-deoxy-D-glucose linked through β-1,4 bonds. The chitosan usedin the present invention may be any of one having a degree ofdeacetylation of 40 to 60% by mole, one having a degree of deacetylationof 60% by mole or more and so forth. It is by no means limited by theorganism from which it is derived, purification method, anddeacetylation method and so forth. To increase disintegrability in thelower gastrointestinal tract, the degree of deacetylation is preferably60 to 98% by mole.

The polymer <B> may be contained in the composition of the presentinvention in a ratio of 10 to 99% and may be contained in this system ina ratio of 10 to 99%. In the formed product of the present invention, itmay be used in a ratio of 10 to 99%. In the case where it is used in thecoating film, it is preferred that it be used in a ratio of 10 to 80% inthe coating film. The “%” as used herein is % of weight per weight andvalues each based on dry weight.

When using the polymers <B> are used in combination, a blending amountratio of, for example, natural cationic polymer and synthetic cationicpolymer may be 99/1 to 1/99. The blending ratio is preferably 99/1 to30/70 and more preferably 99/1 to 50/50.

In the composition for disintegration in lower gastrointestinal tractaccording to the present invention, in addition to the above-mentionedcomponents, a substance that controls disintegration rate in lowergastrointestinal tract may be added. The substance that controls thedisintegration rate includes a substance for imparting resistance sothat the composition will not disintegrate in the small intestine and asubstance that accelerates the disintegration of the composition inlower gastrointestinal tract. The substance for imparting resistance todisintegration in the small intestine includes water-insoluble polymersuch as ethylcellulose, agar, pectin metal salt, carrageenan,crosslinked polysaccharide or protein, or hydrophobic polymer that isacid soluble and is difficult to be swelled with water, such asdimethylaminoethyl methacrylate/methyl methacrylate/butyl methacrylatecopolymer or polyvinyl acetal diethylaminoacetate. The substance thataccelerates the disintegration in lower gastrointestinal tract includespolymers such as gelatin, pectin, starch, and cellulose. The substancesthat control the disintegration rate may be used alone or a combinationof two or more of them may be used in the composition for disintegrationin lower gastrointestinal tract according to the present invention.

On the other hand, in the case of drugs having high water solubility, itmay happen that the drug is leaked as a result of gradual penetration ofwater in spite of imparting resistance to disintegration. In this case,to prevent the penetration of water, a water-repellent substance such asmagnesium stearate may be added to the segment containing the drug or asubstance such as a hydrogenated oil may be coated around the segmentcontaining the drug, so that the leakage of the drug can be prevented.

The substance for imparting resistance to the disintegration in thesmall intestine can prevent swelling or dissolution of polymers, forexample, the polymer <B> in the composition in the small intestine. Inthe case where the substance that accelerates the disintegration inlower gastrointestinal tract is simultaneously added to the composition,decomposition of the composition by gastrointestinal enzymes (forexample, digestion of gelatin by protease) can be prevented.

The substance that accelerates the disintegration in lowergastrointestinal tract is a polymer that is decomposed by protease,lysozyme or a polysaccharide-decomposing enzyme of the enterobacteriaand can accelerate disintegration of the composition.

The addition amount and blending ratio of the substances that controlthe disintegration rate in lower gastrointestinal tract may greatlydiffer depending on the composition for disintegration in lowergastrointestinal tract according to the present invention and formthereof.

The substance for imparting resistance to the disintegration in thesmall intestine may be contained in the composition of the presentinvention in a ratio of 0.1 to 80%. In the formed product, it may beused in a ratio of preferably 0.1 to 80%. In the coating film, it may beused in a ratio of preferably 0.1 to 70%. The substance that acceleratesthe disintegration in lower gastrointestinal tract may be contained inthe composition of the present invention in a ratio of 0.1 to 80%. Inthe formed product, it may be used in a ratio of preferably 0.1 to 80%.In the coating film, it may be used in a ratio of preferably 0.1 to 70%.The “%” as used herein is % of weight per weight and values each basedon dry weight.

The method for producing the composition for disintegration in lowergastrointestinal tract according to the present invention includes, forexample, a method in which a suspension containing the compound <A> anda solution containing the polymer <B> are mixed and dried, a method inwhich the compound <A> is dispersed in a solution containing thecompound <B> and dried, and a method in which the compound <A> and thepolymer <B> are mixed, a suitable solvent is added thereto to dissolvethe polymer <B> therein, and the mixture is made uniform and then dried.

Furthermore, to the composition for disintegration in lowergastrointestinal tract may be added a substance for controlling itsdisintegration rate. In that case, the method for the addition includesa method in which a solution or suspension obtained by dissolving orsuspending a substance for controlling disintegration rate in a suitablesolvent with optional heating, a suspension containing the compound <A>,and a solution containing the polymer <B> are mixed optionally under thecondition of heating and then dried, a method in which a suspension ofthe compound <A> and a solution of the polymer <B> are mixed with asolution or suspension obtained by dissolving with heating or suspendingthe substance for controlling disintegration rate optionally underheating conditions and the mixture is dried, a method in which thecompound <A>, the polymer <B> and the substance for controllingdisintegration rate are mixed, a suitable solvent is added to dissolveor suspend the polymer <B> and the substance for controllingdisintegration rate with optional heating, and the mixture is madeuniform and dried, and so forth. The solvent used for the production iswater or acid solution that is pharmaceutically usable.

Upon drying the composition of the present invention, the drying isperformed by natural drying or by blowing under heating. For example,the composition is dried while spraying or it is coated on an objectiveproduct and dried. Also, for example, if the composition contains athermoplastic substance, the composition is cooled and solidified beforeit can be dried. At the time of production, it is important to take thefollowing into consideration. That is, during the drying or after thedrying, (1) in the case where a volatile acid is used in the productionprocess, humidification treatment increases the efficiency of removingthe acid, (2) the efficiency of drying can be increased by suitablyusing an organic solvent, and so forth.

In these production methods, a substance that is desired to be deliveredto lower gastrointestinal tract may be added before drying.

A formed product or article can be obtained by forming the compositionfor disintegration in lower gastrointestinal tract into a suitable format the time of the drying by the above-mentioned method. By use of asuitable mold at the time of drying the formed product, the compositionmay be formed into various forms such as a needle, a rod, microfineparticles, a sponge, a ring and so forth. The formed products of thepresent invention are those that can be formed by wet forming such as acapsule, a film, a sheet, a coating film for use in preparation, fiber,a rod-like product, granules, powder, and so forth for containing theactive ingredient. Also, the formed products of the present inventioninclude processed products of these, that is, non-woven fabric sheet,woven or knitted fabric, flocks, and coatings on other materials.

In the present invention, the compound <A> can be used in a state ofpowder, suspension (including particulates suspension) or solution. Thepowder containing the compound <A> is preferably adjusted so as to havea suitable particle size by, for example, a ball mill before it can beused. The particles that contain the compound <A> are used at a particlesize of 100 μm or less and more preferably 50 μm or less. When in use inthe composition for disintegration in lower gastrointestinal tractaccording to the present invention, chitosan as the compound <B> may beused after being dissolved in a dilute acid solution. In the case wherechitosan is used after being dissolved, the solvent for chitosan mayinclude solutions of hydrochloric acid, acetic acid, lactic acid, citricacid, malic acid, tartaric acid, glutamic acid, aspartic acid and thelike. However, in the case where the acid is removed by thehumidification treatment as described above, it is preferable to useacetic acid that is a volatile acid. It is preferred that the blendingweight ratio of the acid and chitosan is 30/70 to 99/1. Theconcentration of the chitosan solution is not particularly limited asfar as it has a viscosity that allows production. However, it ispreferable that the chitosan solution has a viscosity of 1 to 1,000 cpsas a 1% by weight solution (1% acetic acid). To adjust the viscosity ofthe chitosan solution, chitosan solutions of different viscosities maybe mixed and their mixing ratio may be set optionally. Degree ofdeacetylation and viscosity may be set optionally in combination.

In the case where a synthetic cationic polymer is used as the compound<B>, it may be used by dissolving it in a water-soluble organic solventsuch as alcohol or acetone or a water-insoluble organic solvent such aschloroform, methylene chloride, or ethyl acetate, besides the acids.

In the case where chitosan and synthetic cationic polymer are used incombination, they may be dissolved in an acid solution or afterdissolving chitosan in an acid solution, a solution of a syntheticcationic polymer in a water-soluble organic solvent may be addedthereto. The water-soluble organic solvent includes preferably loweralcohols such as methanol, ethanol, and isopropanol and acetone. If theaddition amount of the water-soluble organic solvent is too high,chitosan is precipitated, so that the ratio of the water-soluble organicsolvent to the acid solution is preferably 1/99 to 50/50.

The formed product for releasing the contents selectively in lowergastrointestinal tract, comprising a formed of the composition fordisintegration in lower gastrointestinal tract characterized bycomprising the polymer <A> and the polymer <B> as described herein willbe explained.

The formed product has mainly the following forms (1), (2) and (3). (1)includes a sealed vessel-like form for isolating the contents from theouter environment. This is, for example, the case where powdery orgranular contents are sealed. Typical example of such includes acapsule. (2) includes a form that envelops the contents. For example, afilm that coats tablets or granules or a soft capsule that contains aliquid content and so forth may be mentioned. Typical examples thereofinclude a film, a sheet or a coating film used for preparations and soforth. (3) includes the case where the contents are containedsimultaneously, for example the case where the formed product containsthe contents.

The function of the formed product is as follows. After it is moved tothe lower gastrointestinal tract, holes are formed in the formed productas triggered by the reduction reaction by the enterobacteria floraincreasing in the lower gastrointestinal tract, so that the contents arepenetrated therethrough or the formed product is disintegrated, therebyreleasing the contents to the outside site-selectively in thegastrointestinal tract.

More particularly, the compound <A> that exists on the surface of theformed product is decomposed relatively quickly, which increaseswater-solubility of the decomposed product and/or makes the acidity ofthe decomposed product stronger than that of the compound <A>. As aresult, microfine holes are formed in the formed product containing thecompound <A> and the polymer <B>. This accelerates penetration of waterin the lumina therein or serves for sufficient penetration ofenterobacteria to increase disintegrability of the polymer <B>. That is,the polymer <B> is decomposed by the enterobacteria and/or softened,swelled or dissolved. That is, as a result of formation of a largenumber of microfine holes in the portion where the compound <A> waspresent, the polymer <B> is decomposed by the enterobacteria and/orsoftened, swelled or dissolved due to a decrease in pH. On thisoccasion, preferably the effect of decomposition by enterobacteria andthe effect of softening, swelling or dissolving due to a decrease in pHsimultaneously take place and the formed product is disintegrated morequickly and at a more high rate to release the contents to the outside.

The formed product preferably is a) a formed product for releasing acontent in lower gastrointestinal tract, comprising a formed product ofa composition for disintegration in lower gastrointestinal tractcharacterized by containing the compound <A> and the polymer <B>, b) aformed product for releasing a content in lower gastrointestinal tract,comprising a formed product of a composition for disintegration in lowergastrointestinal tract characterized by containing the compound <A>, thepolymer <B> and a substance that controls disintegration rate of thecomposition in lower gastrointestinal tract, c) a formed product forreleasing a content in lower gastrointestinal tract, comprising a formedproduct of a composition for disintegration in lower gastrointestinaltract characterized by dispersing a domain that contains the compound<A> in a matrix containing the polymer <B> in the formed product, or d)a formed product for releasing a content in lower gastrointestinaltract, comprising a formed product of a composition for disintegrationin lower gastrointestinal tract characterized by containing in theformed product a domain that contains the compound <A>, at least thepolymer <B> and a substance that controls disintegration rate of thecomposition in lower gastrointestinal tract.

The polymer <B> used in the formed products may be used alone or incombination as described above.

The term “formed product” means a material obtained by forming thecomposition for disintegration in lower gastrointestinal tract into asuitable form. The formed product includes formed materials such as acapsule, a film, a sheet, a coating film for use in preparation, fiber,a rod-like product, granules, and powder, and so forth for containingthe active ingredient. Further, the formed product includes a materialobtained by coating a composition containing a material desired to bedelivered to a lower gastrointestinal tract with a composition fordisintegration in lower gastrointestinal tract.

When drying the formed products of the present invention, the drying isperformed by natural drying or by blowing under heating. For example,the composition is dried while spraying or it is coated on an objectiveproduct and dried. Also, for example, if the composition contains athermoplastic substance, the composition is cooled and solidified beforeit can be dried. At the time of production, it is important to take thefollowing into consideration. That is, during the drying or after thedrying, (1) in the case where a volatile acid is used in the productionprocess, humidification treatment increases the efficiency of removingthe acid, (2) the efficiency of drying can be increased by suitablyusing an organic solvent, and so forth.

The method for coating the composition for disintegration in lowergastrointestinal tract in particular when forming a formed productincludes a method of spraying a solution containing the polymer <B> inwhich the compound <A> is uniformly dispersed and drying, as prepared bythe above-mentioned method, a method of dipping a material to be coatedin a solution containing the polymer <B> in which the compound <A> isuniformly dispersed, as prepared by the above-mentioned method, and thendrawing it out and drying it, and a method of enveloping by a method forproducing a soft capsule.

In the case where the coating of formed product or article is performedby spraying and drying the surface of tablets, capsule and granules, thecoating may be performed by use of a method in which the preparation ispreliminarily stirred in an apparatus such as coating pan or the like inthe case of a tablet and a capsule or a fluidized bed granulator or arolling layer granulator in the case of granules, and a solutionobtained by uniformly dispersing the compound <A> in a solutioncontaining the polymer <B> is sprayed to the preparation through a spraynozzle and dried.

In the case where the coating of the formed product is performed bydipping the material to be coated, which is used mainly for coating thesurface of a hard capsule, the coating is possible by use of a method inwhich a hard capsule is molded with a molding pin and dried, and then itis dipped in a solution obtained by uniformly dispersing the compound<A> in a solution containing the polymer <B> and dried. Also, a hardcapsule may be produced by directly dipping the molding pin in asolution obtained by uniformly dispersing the compound <A> in a solutioncontaining the polymer <B> and then drawing it out and drying it.

Upon coating the hard capsule, it is preferred that seal treatment bepracticed in advance in order to completely coat the bonded portion.

After performing the coating and drying, humidification treatment isoptionally performed to remove the acid in the coating, so that theresistance in the small intestine can be increased.

For example, in the case where chitosan is a component, humidificationfor removing a volatile acid can be performed, for example, under theconditions of 30 to 40° C. and relative humidity of 60 to 75% for atreating time on the order of 24 to 100 hours.

A soft capsule can be produced by adding cystine as the compound <A>,chitosan as the polymer <B>, agar as the water-insoluble polymer,gelatin as the polymer for accelerating disintegration in lowergastrointestinal tract, and so forth as film forming components andusing an ordinary method such as a rotary die method or a drip in oilmethod (seamless method).

Upon producing a soft capsule, it is desirable to add a thermoplasticsubstance, for example, agar besides the compound <A> and the polymer<B> in order to impart resistance in small intestine. Further, in orderto control disintegration in lower gastrointestinal tract, it isdesirable to add a thermoplastic substance, for example, agar or gelatinbesides the compound <A> and the polymer <B>.

A specific production method for a seamless soft capsule is illustratedhereinbelow. Cystine is dispersed in a solution obtained by adding waterto agar and heating the mixture for dissolution, and further gelatin isadded thereto and dissolved. Then, a chitosan solution separatelydissolved by addition of an acid is added and made uniform suspension.This is used as a film forming liquid. The temperature of the filmforming liquid is preferably 80° C. or less and more preferably 70° C.or less, in order to prevent the degradation of the components. Theviscosity of the film forming liquid is 300 cps or less, and morepreferably 250 cps or less, at 70° C. The content liquid is produced bydissolving or suspending a drug in an oil or fat or emulsifying anaqueous solution of a drug with oil or fat. In the case where a triplenozzle is used as described above, the aqueous solution as it is may beused as the content solution. A content solution is discharged frominside of a double or triple nozzle and a film forming liquid isdischarged from outside thereof into the oil liquid each by use of ametering pump at a constant rate, and the discharged liquid is cut at aconstant interval by means of a certain type of a physical force such asoscillation, impact, a difference in discharge rate between the capsuleliquid and oil liquid to thereby produce spherical seamless softcapsules of 0.1 to 20 mm in diameter through a surface tension betweenthe oil liquid and film forming liquid.

What is described above mainly illustrates an example applied to theseamless soft capsule of the present invention. However, the presentinvention is also applicable to a hard capsule, a rotary die capsule,and other soft capsules.

In the case where the formed product of the present invention is aformed product composed of the compound <A> and the polymer <B>, it isdesirable that it be treated with an alkali or a water-solublealcohol-based organic solvent, or subjected to humidification treatmentin order to impart resistance thereto so as not to disintegrate in thesmall intestine.

The system of the present invention is a system prepared by use of thecomposition for disintegration in lower gastrointestinal tractcharacterized by containing the compound <A> and the polymer <B> and anenteric polymer film, for orally uptake of a material desired to bedelivered to the lower gastrointestinal tract (for example, activeingredient <C> or bacteria cell such as bifido bacteria or the like) andfor the release of it selectively in lower gastrointestinal tract.

Further, the system of the present invention, which may be either coatedwith the composition for disintegration in lower gastrointestinal tractor contained in the composition, is preferably further coated with anenteric polymer film. Furthermore, the composition for disintegration inlower gastrointestinal tract used in the system of the present inventionis preferably a dispersion of a domain containing the compound <A> in amatrix containing the polymer <B>.

The polymer <B> used in the system of the present invention may be usedalone or in combination as described above.

The system of the present invention includes not only a preparation thatcomprises composition for disintegration in lower gastrointestinaltract, more particularly a formed product using the composition, and anenteric polymer film and releases the active ingredient <C> selectivelyin lower gastrointestinal tract but also a sustained releasepreparation, a diagnostic method and a material for use therein, and afunctional food and so forth. For example, the system of the presentinvention includes the preparations having the above-mentioned featuresas main modes but is not limited to these modes and includes its use ina pulsatile release type sustained preparation as one mode of the systemof the present invention. That is, by combining the preparation forrelease in lower gastrointestinal tract as a slow release unit with aquick release unit, there can be obtained a sustained releasepreparation of which the unit that releases a drug in, for example, thestomach and small intestine disintegrates in series and thereafter theunit that releases a drug in lower gastrointestinal tract disintegrates.Thus, the system of the present invention can be applied to variousdrugs of which sustained release is desired.

Another mode of the system of the present invention finds applicationnot only in the field of treatment but also in the field of diagnostics.For example, a capsule containing a drug such as a contrasting agent canbe used in combination with X-ray and an NMR image forming technique byallowing the drug to be released in lower gastrointestinal tract aftertaking the capsule. In other fields of diagnostics, a would-be antigen(allergen) or allergic food component can be delivered to lowergastrointestinal tract for the diagnostics of allergy. Furthermore, inanother mode, the system of the present invention includes a functionalfood. For example, filling bifido bacteria or a substance that has anactivity of growing bifido bacteria (example; oligosaccharide and soforth) or the like is in a capsule and allowing it to be releasedselectively in lower gastrointestinal tract, the bifido bacteria in thelower gastrointestinal tract can be increased and the activity ofrecovering intestinal order can be utilized.

The “preparation for release in lower gastrointestinal tract” of thepresent invention is a preparation for release in lower gastrointestinaltract characterized in that the composition for disintegration in lowergastrointestinal tract characterized by containing at least the activeingredient <C>, the compound <A> and the polymer <B> is coated with anenteric polymer film. It is a preparation that has a function ofselectively releasing the active ingredient <C> in lowergastrointestinal tract by use of the “composition for disintegration inlower gastrointestinal tract” of the present invention, which is afunctional material that disintegrates selectively in lowergastrointestinal tract, and further by used of an enteric polymer film.

The preparation of the present invention is preferably composed of acomposition containing the active ingredient <C> and a pharmaceuticallyacceptable carrier, and coated with the composition for disintegrationin lower gastrointestinal tract characterized by containing the compound<A> and the polymer <B> and further with an enteric polymer film.Further, in the system of the present invention, the composition fordisintegration in lower gastrointestinal tract used is preferably one inwhich the domain containing the compound <A> is dispersed in the matrixcontaining the polymer <B>.

In the preparation for release in lower gastrointestinal tract of thepresent invention, the polymer <B> may be used alone or in combinationas described above.

The form of the preparation for release in lower gastrointestinal tractof the present invention includes a tablet, a granule, a fine granule, apowder, a capsule, and so forth, and any form may be adopted. Forexample, in the case of a tablet, a compression formed tablet containingan active ingredient may be coated with a film of the composition of thepresent invention. In particular, in order to quickly disperse a drughaving a very high fat solubility, such as steroid, in an environmentwhere there is a small amount of water, such as colon, a form of capsulehaving filled therein a drug in a state of solution or suspension ispreferred. The form of a soft capsule is more preferred in considerationof production costs. The drug that can be encapsulated by a soft capsulegenerally includes drugs having high fat solubility that is readilysoluble in oil or fat. In the case of water-soluble drugs, theencapsulation can be practiced by a method of suspending the drug in oilor fat. In the case where a water-soluble drug is filled in a seamlesscapsule, besides the method of suspending a drug in oil or fat, a methodin which a triple nozzle is used and an oil or fat layer is arrangedbetween an aqueous solution of the drug and a film may be practiced (JP8-10313 A). The preparation of various kinds may be produced by onehaving ordinary skill in the art.

The material desired to be delivered to lower gastrointestinal tract,which the objective material in the present invention, is notparticularly limited.

In the case where the system of the present invention is used as afunctional food, it includes, for example, lactic acid bacteriapreparations such as lactomine preparations, bifido bacteria-lactomincompound, butyric acid bacteria, or resistant lactic acid bacteria,lactose decomposing enzyme drugs such as β-galactosidase and tilactase,vitamins and so forth.

In the case where the system of the present invention is used fordiagnosis, it includes chemicals for a contrasting agent, such asamidotrizoic acid or barium sulfate. It is used in combination withX-ray and NMR image forming technology by taking a capsule encapsulatingit therein. It also includes antigens (allergens such as egg, milk,soybean, wheat, peanut, buckwheat, and banana), allergic food components(drug contained in food, colorant, preservative, yeast, bacteria and soforth) and the like for the diagnosis of allergy. It is released inlower gastrointestinal tract when in use.

In the case where the system of the present invention as a medical(animal medical) preparation, the “material desired to be delivered tolower gastrointestinal tract” is as explained in “active ingredient<C>”. The following (1) to (4) may be mentioned of.

-   (1) Therapeutic drugs of which site-specific delivery is desirable    include drugs considered to be effective to diseases in lower    gastrointestinal tract, for example, therapeutical drugs for Crohn's    disease, ulcerative colonitis, colon cancer and the like. Specific    examples thereof include

5-ASA derivatives such as mesalazine, 5-aminosalycilic acid (5-ASA), andsalazosulfapyridine, steroids such as cortisone acetate, triamcinolone,dexamethasone, hydrocortisone, prednisolone, betamethasone,betamethasone valerate, paramethasone acetate, fludrocortison acetate,halopredone acetate, fluocinolone acetonide, fluocinonide, andhydrocortisone acetate, antedrug type steroids such as budesonide,beclometasone dipropionate, fluticason propionate, and betamethazondipropionate.

Immunosuppressors such as cyclosporin, 6-mercaptopurine, tacrolimus,azathioprine, and mizoribine, protease inhibitors such as ulinastatinand camostat mesilate, highly unsaturated fatty acids such as EPA andDHA and esters thereof, anticancer agents such as tegafur, fluorouraciland bleomycin,

Antirheumatic agents such as sodium aurothiomalate, penicillamine,auranofin, disodium lonzarit, and actariot, antathmatic agents such asbeclometazone propionate, hemostats such as carbazochrom sodiumsulfonate, adrenochrome guanylhydrazone mesilate, ethanesylate,ε-aminocaproic acid, tranexamic acid, thrombin, cellulose chloride,gelatin, monoethanolamine oleate, and polycazole, fungicides such asamphotericin B, flucytocine, miconazole, fluconazole, itraconazole, andgriseofulvin, various antibiotics such as β-lactams (penicillins,cephems), amino glucosides, macrolides, tetracyclines, new quinolones,vancomycin, and clindamycin, anti-inflammatory agents such as salicylicacids (sodium salicylate, aspirin, sazapirin, etc.), aryl acetates(diclofenac sodium, tolmethine sodium, fenbufen, indomethacin, amfenacsodium, mebumethone, etc.), propionic acids (ibuprofen, ketoprofen,naproxene, loxoprofen sodium, etc.), fenamic acids (flufenamic acid,mefenamic acid, floctafenin, tolfenamic acid, etc.),pyrazolones(ketophenylbutazone, etc.), and oxicams (piroxicam,ampiroxicam, etc.), local anesthetics such as procaine hydrochloride,oxyprocaine hydrochloride, ethyl aminobenzoate, cocaine hydrochloride,tetracaine hydrochloride, lidocaine hydrochloride, dibucainehydrochloride, protocaine hydrochloride, and oxazane, enterokinesisaccelerators such as cisapride.

-   (2) The material desired to be delivered to lower gastrointestinal    tract directly includes, for example, a laxative and an    antidiarrhetic. It is desirable that these be released selectively    in the colon. Specific examples of cathartics include large    intestine stimulating cathartics, for example, anthraquinone    derivatives contained in galenicals such as senna, rhubarb and aloe,    phenolphthalein derivatives such as phenovaline, diphenyl    derivatives such as laxoberon, large intestine stimulating    cathartics such as bisacodyl, and small intestine stimulating    cathartics such as castor oil and olive oil, and so forth. Specific    examples of antidiarrhetics include astringents such as albumin    tannate and bismuth formulations, bactericides such as berberine    chloride and berberine chloride arranged formulations, enterokinesis    inhibitors such as opium alkaloid, mepenzolate bromide    (parasympatholytic drug/cholinolytic drug), loperamide chloride,    trimebutine maleate, oxethazaine, tiquizium bromide, and cisapride.-   (3) Also a drug that could cause gastrointestinal injury in upper    gastrointestinal tract due to its direct action to the gastric wall,    for example, a nonsteroidal anti-inflammatory drug (NSAID) can be    released selectively in lower gastrointestinal tract and allowed to    be absorbed thereby. Specific examples thereof include salicylic    acids (sodium salicylate, aspirin, sazapirin, etc.), aryl acetates    (diclofenac sodium, trimethine sodium, fenbufen, indomethacine,    amfenac sodium, mebutone, etc.), propionic acids (ibuprofen,    ketoprofen, naproxen, loxoprofen sodium, etc.), fenamic acids    (flufenamic acid, mefenamic acid, floctafenine, trifenamic acid,    etc.), pyrazolones (ketophenylbutazone, etc.), oxicams (piroxicam,    ampiroxicam, etc.) and the like anti-inflammatory agents.-   (4) Various physiologically active polypeptides, proteins and    derivatives thereof of which decomposition in upper gastrointestinal    tract (peptide), in particular decomposition in upper    gastrointestinal tract have to be inhibited, for example, insulin,    calcitonin, angiotensin, vasopressin, desmopressin, LH-RH    (luteinizing hormone-releasing hormone), somatostatin, glucagon,    oxytocin, gastrin, cyclosporin, somatomedin, secretin, h-ANP (human    atrial sodium diuretic peptide), ACTH (adrenocorticotropic hormone),    MSH (melanophore stimulating hormone), β-endorphin, muramyl    dipeptide, enkephalin, neurotensin, pombesin, VIP (vasoactive    intestinal polypeptide), CCK-8 (cholecystokinin-8), PTH (parathyroid    hormone), CGRP (calcitonin gene related peptide), TRH (thytropin    releasing hormone), endothelin, hGH (human growth hormone), and    cytokines such as interluekins, interferons (α, β and γ), colony    stimulating factor, and tumor necrosis factor, and derivatives    thereof. The peptides and proteins include not only those derived    from natural substances but also pharmacologically active    derivatives and analogues thereof (for example, mutants with    deletion, substitution or addition by genetic recombination).    Therefore, calcitonin, which is an objective in the present    invention includes not only naturally occurring products such as    salmon calcitonin, human calcitonin, porcine calcitonin, eel    calcitonin, and chicken calcitonin but also analogues thereof such    as [Asul, 7]-eel calcitonin (elcatonin). Insulin not only includes    human insulin, porcine insulin, and eel insulin but also includes    their analogues such as their genetic recombinants.

In the present invention, the material desired to be delivered in lowergastrointestinal tract may be used alone or as mixtures of two or moreof them, or may be mixed with pharmaceutically acceptable carriers.

Further, drugs that have high first pass effects when they are absorbedin the small intestine or that have decreased bioavailability because ofinhibited absorption due to the interaction with undigested food orcomponents of gastrointestinal juice in the small intestine arepreferred examples of the active ingredient of the present invention.The drugs that are influenced by the drug-metabolizing enzyme in theupper gastrointestinal tract when absorbed in the small intestine arepreferred examples of drugs that are released and absorbed in therectum, portion of the large intestine.

The materials that are desired to be delivered to the lowergastrointestinal tract may be optionally mixed with other additives thathave been accepted as drug additives and food additives, or may becontained in an oil base.

The “enteric polymer film” is an enteric film made from a polymer thatis soluble in a liquid at a pH 5 or more as a base material. It is notparticularly limited as far as it is selected from various enteric basematerials that can impart resistance to gastric juice when they are usedin the preparation of the present invention and that have been widelyused conventionally. In the system of the present invention, it ispreferred that an enteric film is provided on the outermost layer inorder to protect the polymer that is dissolved in an acidic state fromthe low pH environment in the stomach. Specific examples of the basematerial used for such an enteric coating film include anionic acrylicresins such as methacrylic acid/methyl acrylate copolymer andmethacrylic acid/ethyl acrylate copolymer (for example, Eudragit L,Eudragit S (both trade names; Roehm, Germany), etc.),hydroxypropylmethylcellulose acetate succinate (HPMCAS),hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetatephtalate (CAP), hydroxypropylmethylcellulose (HPMC),carboxymethylcellulose acetate phthalate (CMCAP), shellac, and so forth.Mixtures of these may also be used. The enteric coating film may be usedby coating to form a film layer in an ordinary method. Also, it may beused in the form of a capsule produced using the base material. That is,a soft capsule using the composition for disintegration in lowergastrointestinal tract containing at least the compound <A> and thepolymer <B> according to the present invention, which is a constituentunit for releasing the active ingredient in lower gastrointestinaltract, may be placed in a capsule of an enteric coating film before itcan be used.

The term “coated” as used herein includes not only the state of beingcoated to form a coating film but also the state of being placed in, forexample, the capsule that is made with the polymers as described above.

In the system of the present invention, one or more pharmaceuticallyacceptable additives may be added in order to facilitate its absorptionor dispersion in the lower gastrointestinal tract. Such an additiveincludes oil or fat, a surfactant, a medium chain aliphatic carboxylicacid and its salt, EDTA, and various protease inhibitors for preventingenzymatic decomposition in the colon in the case of absorption ofpeptide or the like. Examples of the oil or fat include medium chainfatty acid triglycerides (migliore, etc.), hard fat (Witep sol, etc.),and vegetable oil (olive oil, etc.). The surfactant includes, forexample, various bile acid salts, sodium lauryl sulfate, sucrose fattyacid esters, sorbitan fatty acid esters, polyoxysorbitan fatty acidesters (Tween 80, etc.), polyoxyethylene hardened castor oil (HCO60,etc.), polyoxyethylene lauryl ether, polyethylene glycol fatty acidester and/or mixtures of these with glyceride (for example, trade name;GELSIE (Gatefoce, France), and so forth. The medium chain aliphaticcarboxylic acid includes caproic acid, caprylic acid, capric acid,lauric acid, myristic acid, and so forth. Their salts are typicallysodium salts and potassium salts. The protease inhibitor includesaprotinin, ulinastin, camostat mesilate and so forth.

Particularly preferable combinations of constituent elements of thecomposition for disintegration in lower gastrointestinal tract, formedproduct using the composition, preparation or system for release inlower gastrointestinal tract using them will be described hereinbelow.However, the present invention should not be construed as being limitedthereto.

Particularly preferred examples of the composition for disintegration inlower gastrointestinal tract include a) a composition for disintegrationin lower gastrointestinal tract characterized by containing cystine andat least chitosan, b) a composition for disintegration in lowergastrointestinal tract characterized by containing cystine and at leastchitosan and a substance that controls disintegration rate in lowergastrointestinal tract, c) a composition for disintegration in lowergastrointestinal tract characterized in that a domain containing cystineis dispersed in a matrix containing at least chitosan, and d) acomposition for disintegration in lower gastrointestinal tractcharacterized in that a domain containing cystine is dispersed in amatrix containing at least chitosan and a substance that controlsdisintegration rate in lower gastrointestinal tract.

Particularly preferred examples of the formed product include a) aformed product for releasing a content in lower gastrointestinal tract,comprising a formed product of the composition for disintegration inlower gastrointestinal tract characterized by containing cystine and atleast chitosan, b) a formed product for releasing a content in lowergastrointestinal tract, comprising a formed product of composition fordisintegration in lower gastrointestinal tract characterized bycontaining cystine and at least chitosan and a substance that controlsdisintegration rate in lower gastrointestinal tract, c) a formed productfor releasing a content in lower gastrointestinal tract, comprising aformed product of composition for disintegration in lowergastrointestinal tract characterized in that a domain containing cystinein the formed product is dispersed in a matrix containing at leastchitosan, and d) a formed product for releasing a content in lowergastrointestinal tract, comprising a formed product of composition fordisintegration in lower gastrointestinal tract characterized in that adomain containing cystine in the formed product is dispersed in a matrixcontaining at least chitosan and a substance that controlsdisintegration rate in lower gastrointestinal tract.

Particularly preferred examples of the preparation include i) apreparation for release in lower gastrointestinal tract characterized inthat a composition for release in lower gastrointestinal tractcharacterized by containing cystine and at least chitosan and an activeingredient <C> are coated with an enteric polymer film, ii) apreparation for release in lower gastrointestinal tract characterized inthat a composition containing an active ingredient <C> and apharmaceutically acceptable carrier is coated with a composition fordisintegration in lower gastrointestinal tract characterized bycontaining cystine and at least chitosan and further coated with anenteric polymer film, and iii) a preparation for release in lowergastrointestinal tract characterized in that a composition containing anactive ingredient <C> and a pharmaceutically acceptable carrier iscoated with a composition for disintegration in lower gastrointestinaltract characterized in that a domain containing cystine in thecomposition is dispersed in a matrix containing cystine and at leastchitosan and further coated with an enteric polymer film.

Particularly preferred examples of the system include i) a system forperoral uptake of a material desired to be delivered to lowergastrointestinal tract and selective release in the lowergastrointestinal tract, characterized in that a composition fordisintegration in lower gastrointestinal tract characterized bycontaining cystine and at least chitosan and an enteric polymer film areused, ii) a system for peroral uptake of a material desired to bedelivered to lower gastrointestinal tract and selective release in thelower gastrointestinal tract, characterized in that the material desiredto be delivered to the lower gastrointestinal tract is coated with oradded to a composition for disintegration in the lower gastrointestinaltract characterized by containing cystine and at least chitosan, andfurther is coated with an enteric polymer film, and iii) a system forperoral uptake of a material desired to be delivered to lowergastrointestinal tract and selective release in the lowergastrointestinal tract, characterized in that a composition containingan active ingredient <C> and a pharmaceutically acceptable carrier iscoated with a composition for disintegration in lower gastrointestinaltract characterized in that a domain containing cystine in thecomposition is dispersed in a matrix containing cystine and at leastchitosan and further coated with an enteric polymer film.

The above-mentioned chitosan used in particularly preferred combinationsof constituent elements of the composition for disintegration in lowergastrointestinal tract, formed product, preparation for release in lowergastrointestinal tract or system of the present invention may be usedalone or in combination as described above. By using a syntheticcationic polymer, for example, an acid-soluble hydrophobic polymer, incombination, swelling of chitosan with water can be inhibited and itswater resistance can be increased further.

The compounding weight ratio of cystine to chitosan may be setoptionally. However, it is preferred to set it in the range of 10/90 to90/10. It is preferred that the compounding weight ratio of agar togelatin be set in the range of 10/90 to 90/10. Further, the totalcompounding weight of agar and gelatin is preferably 5% or more based onthe total weight of the capsule film (% of weight per weight; value ondry basis).

The adaptation diseases targeted by the system for peroral uptake of amaterial desired to be delivered to lower gastrointestinal tract andselective release in the lower gastrointestinal tract according to thepresent invention are not particularly limited as far as they are basedon the main medicinal effect. The diseases may be coped with by eithersystemic administration or local administration. The diseases intendedto be coped with by local administration include lower gastrointestinaltract diseases (ulcerative colonitis, Crohn's disease, colorectalcancer, colon cancer, colorectal polyps, irritable colonitis, irritablebowel syndrome, etc.). The system of the present invention may be usedalso as preparations such as an enteral flora-forming agent, ahemorrhoids treating agent, an intestinal disorder treating agent, and acathartic.

Next, the present invention and effects thereof will be illustrated inmore detail with reference to examples and test examples.

Example 1

50 ml of water was added to 1 g of agar, 1 g of cystine, and 1 g ofglycerol, and the mixture was stirred at 90° C. to dissolve the agar.After the temperature of the resultant suspension was decreased to 70°C., 1.5 g of gelatin was added and the mixture was stirred to dissolve.Further, a solution of 1.5 g of chitosan (Chitosan LL (registeredtrademark), viscosity (0.5%, 20° C.); 20 cps or more, Yaizu Suisan), and0.5 g of acetic acid in 25 ml of water was added thereto and stirred toobtain a uniform suspension.

7 ml of this suspension is spread in a dish of 9.3 mm in inner diameterand dried to prepare a cast film (about 60 μm in film thickness).

Example 2

50 ml of water was added to 1 g of agar, 1 g of cystine, 1 g ofglycerol, and 1 g of corn starch and the mixture was stirred at 90° C.to dissolve the agar and corn starch. Then, the temperature of theresultant suspension was decreased to 70° C. Further, a solution of 1.5g of chitosan (Chitosan LL (registered trademark), viscosity (0.5%, 20°C.); 20 cps or more, Yaizu Suisan), and 0.5 g of acetic acid in 25 ml ofwater was added thereto and stirred to obtain a uniform suspension.

7 ml of the suspension was spread in a dish of 9.3 mm in inner diameterand dried to prepare a cast film (about 60 μm in film thickness).

Comparative Example 1

50 ml of water was added to 1 g of agar, 1 g of β-cyclodextrin, 1 g ofglycerol, and 1 g of corn starch and the mixture was stirred at 90° C.to dissolve the agar and corn starch. Then, the temperature of theresultant suspension was decreased to 70° C. Further, a solution of 1.5g of chitosan (Chitosan LL (registered trademark), viscosity (0.5%, 20°C.); 20 cps or more, Yaizu Suisan), and 0.5 g of acetic acid in 25 ml ofwater was added thereto and stirred to obtain a uniform suspension.

7 ml of the suspension was spread in a dish of 9.3 mm in inner diameterand dried to prepare a cast film (about 60 μm in film thickness).

Example 3

100 ml of water was added to 2 g of agar, 8 g of cystine, and 8 g ofglycerol, and the mixture was stirred at 90° C. to dissolve the agar.After the temperature of the resultant suspension was decreased to 70°C., 10 g of gelatin was added and the mixture was stirred to dissolvegelatin. Further, a solution of 6 g of chitosan and 6 g of citric acidin 60 ml of water was added thereto and stirred to obtain a uniformsuspension. Then seamless soft capsules having a particle size of about2.4 mm and a weight of about 8.9 mg (content of about 5.3 mg) wereproduced by a drip in oil method using the suspension as a film formingliquid and a solution (0.25 mg/g) of fat-soluble red dye Sudan IVdissolved in a medium chain fatty acid triglyceride (MCT) as a contentliquid. As the chitosan, a 2.8:3.2 mixture of Chitosan LL (registeredtrademark) (viscosity (0.5%, 20° C.); 20 cps or more, Yaizu Suisan) andChitosan 100 (registered trademark) (viscosity (0.5%, 20° C.); 90.2 cps,Wako) was used.

Example 4

In the same manner as in Example 3, seamless capsules having a particlesize of about 2.4 mm and a weight of about 8.7 mg (content of about 5.9mg) were produced using a suspension (50 mg/g) of indomethacinedispersed in a medium chain fatty acid triglyceride (MCT) as a contentliquid.

Test Example 1

The cast films obtained in Examples 1, 2 and comparative Example 1 wereplaced in a sealed vessel containing a suspension of cecum contents of aWistar rat (30 g (wet weight) of cecum contents/60 g of pH 6.8 carbonatebuffer) or pH 6.8 carbonate buffer to dip therein and the space waspurged with carbon dioxide gas. Thereafter, the vessel was sealed andweakly shaken at 37° C. for 16 to 20 hours. After the shaking, the castfilms were taken out, washed with water and dried. The surface of eachcast film was observed on a scanning electron microscope at amagnification of 1,000 times.

The carbonate buffer was prepared by weighing respective components,dissolving them in a suitable amount of water, making the total amountto 1 liter and bubbling CO₂ into the solution to adjust it to pH 6.8.NaHCO₃ 9.240 g Na₂HPO₄.12H₂O 7.125 g NaCl 0.470 g KCl 0.450 g CaCl₂.2H₂O0.073 g MgCl₂.6H₂O 0.087 g H₂O suitable amount Total amount 1 liter.

The cast film in Comparative Example 1 had a smooth surface and nocorrosion was observed after dipping it in the suspension of cecumcontents. On the contrary, deep corrosion was observed in the cast filmof Example 1 and the corrosion further proceeded in the cast film ofExample 2. Furthermore, no corrosion was observed in the cast films ofExamples 1 and 2 with dipping in the carbonate buffer.

Here, “corrosion” refers to the state where a part of the film isdetached from the surface of film due to decomposition or dissolution toform a groove or hole. The results are shown in FIGS. 1 to 4, which arescanning electron micrographs.

FIG. 1(a) The cast film of Example 1

-   -   Before the test

FIG. 1(b) Example 1

-   -   In carbonate buffer    -   16 Hours (37° C.)

FIG. 2 Example 1

-   -   In suspension of cecum contents    -   16 Hours (37° C.)

FIG. 3(a) The cast film of Comparative Example 1

-   -   Before the test

FIG. 3(b) Comparative Example 1

-   -   In carbonate buffer    -   20 Hours (37° C.)

FIG. 4 Comparative Example 1

-   -   In suspension of cecum contents    -   20 Hours (37° C.)

Test Example 2

Three seamless soft capsules obtained in Example 3 were filled in anenteric capsule (enteric capsule for animals MGS·AS-M type, FreundSangyo). Enteric capsules thus obtained were orally administered to ratsfed to repletion and rats starved for 20 hours, respectively. In thesate of being fed to repletion, the rats were sacrificed with lapse oftime for 4 to 24 hours and the capsules in the gastrointestinal tractwere observed. The results are shown in FIG. 5.

In the instant test, the capsule when the rats were fed to repletion didnot disintegrate and had maintained high strength of the film so that noleakage of the content liquid was observed in the upper gastrointestinaltract to the ileum. Further, high strength of the film was maintained.However, in the cecum and colon, the film strength decreased anddisintegration of capsule and leakage of content liquid were observed.

The film strength was measured as follows. The capsule taken out of thegastrointestinal tract was placed in a dish in which Kim-wipe was laid.Then, a probe of a force gauge (MODEL-9500, produced by Aiko EngineeringCo., Ltd.) attached to a movable stand was actuated in the verticaldirection to push the capsule and maximum load (unit: N) at which thecapsule was broken and the content liquid was leaked was recorded. Whenthe film strength was 0.1 N or less, it was judged that the “filmstrength was decreased”. Unchanged seamless soft capsules had a filmstrength of 0.25 N or more. The blackened seamless soft capsules had afilm strength of 0.1 N or less, so that their film strength wasdecreased.

Example 5

480 ml of water was added to 9 g of chitosan (Chitosan PSH (registeredtrademark) (viscosity (0.5%, 20° C.); 100 cps or more, Yaizu Suisan) todisperse it and then 81 g of acetic acid was slowly added while stirringto dissolve the chitosan.

To this solution was added a solution of 9 g of dimethylaminoethylmethacrylate/methyl methacrylate/butyl methacrylate copolymer (EudragitE(registered trademark), Roem GmbH, Germany) in 300 g of ethanol andfurther a suspension of 9 g of cystine in 100 g of water. The mixturewas stirred to make it uniform. Thus, a suspension was obtained.

7 ml of he suspension was spread in a dish of 9.3 mm in inner diameter,and dried to prepare a cast film.

Comparative Example 2

A cast film was prepared in the same manner as in Example 5 except thatcystine was eliminated from Example 5.

Test Example 3

The cast films prepared in Example 5 and Comparative Example 2 abovewere subjected to shaking test in a suspension of cecum contents andcarbonate buffer in the same manner as in Test Example 1. Digitalmicroscopic images of the results obtained are shown in FIG. 6. FIG.6(a) relates to the cast film prepared in Example 5 and FIG. 6(b)relates to the cast film prepared in Comparative Example 2. In eachimage, the left hand side (film looking white) shows the results ofshaking in the carbonate buffer and the right hand side shows theresults of shaking in the suspension of cecum contents.

The black fragment in mat paper background on the right hand side inFIG. 6(a) shows the cast film obtained from the composition of thepresent invention. It was demonstrated that the film was blackened andcompletely disintegrated by dipping it in the suspension of cecumcontents.

Example 6

The suspension prepared in Example 5 was used as a coating liquid.

In No. 3 gelatin hard capsules provided with a band seal were eachfilled 20 mg of theophylline as a model drug and 40 mg of magnesiumstearate as an leakage inhibitor of theophylline in the small intestine.To this was sprayed the coating liquid prepared as above using a coatingapparatus (Doria Coater 200, Powrex Corporation) to coat the capsules.

Then, the coated capsules were placed in a thermohygrostat set to 40° C.and 75% and subjected to humidification treatment for 24 hours.

Test Example 4

To confirm the resistance in small intestine, the coating capsulesobtained in Example 6 were subjected to elution tests by the paddle testin accordance with Japan Pharmacopoeia Elution Test.

The test solution was Japan Pharmacopoeia second liquid (pH 6.8) andpaddle rotation number was 50 rpm.

In the Japan Pharmacopoeia second liquid, which was a simulatedintestinal juice, the capsules in Example 6 showed a very low leakageratio of theophylline. As a result, it was demonstrated that thecapsules of the present invention showed resistance in the smallintestine. The results obtained are shown below. TABLE 2 Small IntestineResistance Test Elution ratio of theophylline (%) Time No. 1 No. 2Average 0 hr 0 0 0 1 hr 0.3 0.2 0.3 2 hr 1.7 2.0 1.9 3 hr 4.8 5.3 5.1 4hr 7.8 8.2 8.0

Test Example 5

The capsules of Example 6 were placed in a No. 1 enteric capsule (FreundSangyo) and further 10 mg of acetoaminophenone as a marker forindicating arrival at small intestine and 50 mg of sulfasalazine as amarker for indicating arrival at colon were added thereto. The connectedportion of the capsule was sealed with a solution ofhydroxypropylmethylcellulose acetate succinate, which was a raw materialof capsule, in a mixed solution of methylene chloride/ethanol (1:1).

The capsule was orally administered to a dog together with 30 ml ofwater and the dog was collected the blood chronologically and theconcentration of drug in the obtained plasma was measured. The dog wasintravenously injected with atropin sulfate as an enteromotilitysuppressor 30 minutes before the oral administration in order to makeuniform the rate of movement of capsule in the gastrointestinal tract.Sulfasalazine as the marker for indicating arrival at colon wasdecomposed by the enterobacteria after the arrival at the colon torelease sulfapyridine as a decomposition product.

By measuring the blood level of sulfapyridine, an indication of arrivalat colon of capsule was obtained. The blood level changes of the modeldrug and marker substances are shown in FIG. 7.

Since theophylline appeared later than the appearance of sulfapyridinein blood, it was confirmed that the capsule coated in Example 6 hadresistance in small intestine and further that the capsule wasdisintegrated to release the contents after a while after its arrival atthe colon.

As described above, it was demonstrated that the cast films formulatedin soft capsules of the present invention were corroded on their surfaceby dipping them in a suspension of cecum contents. The dry weight of thecast film corroded in the suspension of cecum contents decreased ascompared with the dry weight of the cast film of which no corrosion wasobserved in the carbonate buffer. Further, the seamless soft capsulescontaining cystine and chitosan in the capsule film according to thepresent invention did not disintegrate in the upper gastrointestinaltract to the ileum and no leakage of the content liquid was observed, sothat they had high film strength. In the cecum and colon, the filmstrength of the capsule decreased and disintegration of the capsule andleakage of the content liquid occurred.

It was demonstrated that the cast films formulated in film coatingaccording to the present invention were blackened and disintegratedcompletely by dipping them in the suspension of cecum contents.

The film coating capsules of the present invention showed suppressedleakage of the content liquid in elution tests using Japan Pharmacopoeiasecond liquid and further in the experiment of administration to a dog,they showed retarded release as compared with that of the markerindicating arrival at colon. This indicated that there occurredcolon-specific release.

Therefore, by use of the composition for disintegration in lowergastrointestinal tract according to the present invention, the contentcan be delivered unfailingly, quickly and selectively in lowergastrointestinal tract utilizing enterobacteria that can be consideredto have high specificity for targeting the lower gastrointestinal tractwithout being influenced by a change in pH due to a variation inbacterial flora.

INDUSTRIAL APPLICABILITY

By use of the composition for disintegration in lower gastrointestinaltract according to the present invention, that is, a composition fordisintegration in lower gastrointestinal tract, comprising a compound<A> having a molecular weight of 1,000 or less and having a disulfidebond and a polymer <B> having a molecular weight of above 1,000 andhaving a property of being decomposed by enterobacteria, and/or aproperty of being softened, swelled or dissolved due to a decrease inpH, the content can be delivered unfailingly, quickly and selectively inlower gastrointestinal tract utilizing enterobacteria without beinginfluenced by a change in pH due to a variation in bacterial flora.Therefore, the preparation using the composition for disintegration inlower gastrointestinal tract according to the present invention enableslocal accumulation of the drug in treating local gastrointestinal tractdiseases such as ulcerative colitis and Crohn's disease, and thereforeit is useful for improving the therapeutic effect.

Since no release of drug occurs before arrival at the lowergastrointestinal tract, side effects due to systemic circulation of thedrug are decreased, and loss of the drug before it reaches the sitewhere it is effective can be prevented. Therefore, the present inventionis useful for improving the therapeutic effect.

Since use of the disintegrable composition of the present invention canprolong the residence time i.e., absorption effective time, in thecolon, of a drug that has the property of exhibiting the efficacy afterits transfer in systemic circulation, the colon can be utilized as anabsorption site therefor. The colon secretes no gastrointestinal enzymeand the peptidase activity of mucous membrane of large intestine is lowas compared with that of small intestine. Accordingly, especially apeptide- or protein-based drug, when it is released in the colon, ishardly metabolized by the enzymes, so that higher biologicalavailability can be obtained.

The system for peroral uptake of a material desired to be delivered tolower gastrointestinal tract and selective release in the lowergastrointestinal tract according to the present invention can be used asa preferred example for the improvement of bioavailability for drugsthat show decreased bioavailability due to high first pass effects whenthey are absorbed in the small intestine or due to inhibited absorptionas a result of the interaction with undigested food or components ofgastrointestinal juice in the small intestine. In addition, the drugsthat are influenced by the drug-metabolizing enzyme in the uppergastrointestinal tract when absorbed in the small intestine are used asa preferred example in which a drug is released and absorbed in therectum portion of the large intestine.

Furthermore, the system of the present invention can be used indiagnosis using a sustained release preparation, X-ray and NMR imagingtechnology or in health-care foods (functional foods).

1. A formed product suitable for delivery of an active-ingredient fortherapeutic use, comprising a matrix comprising chitosan and particlesof cystine dispersed in said matrix.
 2. The formed product of claim 1,wherein cystine and chitosan are present in a ratio of 10/90 w/w to90/10 W/W.
 3. The formed product of claim 1, wherein the matrix furthercomprises at least one substance selected from the group consisting ofagar, pectin metal salt, carrageenin, gelatin, pectin, starch,cellulose, dimethylaminoethylmethacrylate/methylmethacrylate/butylmethacrylate copolymer andpolyvinylacetal diethylaminoacetate that controls disintegration rate ofthe formed product in the large intestine of the gastrointestionaltract.
 4. The formed product of claim 1, wherein the formed product isin the form of an empty hard capsule.
 5. The formed product of claim 1,wherein the formed product is in the form of a hard capsule, containingan active-ingredient for therapeutic use in the inside of said hardcapsule.
 6. The formed product of claim 5, wherein the hard capsulefurther comprises an enteric coating on the outside of said hardcapsule.
 7. The formed product of claim 4, 5 or 6, wherein the matrixcontaining chitosan further comprises at least one substance thatcontrols disintegration rate in the large intestine of the lowergastrointestinal tract.
 8. The formed product of claim 7, wherein the atleast one substance that controls the disintegration rate in the largeintestine of the lower gastrointestinal tract is at least one substanceselected from the group consisting of agar, pectin metal salt,carrageenin, gelatin, pectin, starch, cellulose, dimethylaminoethylmethacrylate/methylmethacrylate/butylmethacrylate copolymer andpolyvinylacetal diethylaminoacetate.
 9. A method for delivering amaterial to a large intestine part of lower gastrointestinal tract of apatient, comprising the step of: orally administering the formed productof claim 6 to a patient.
 10. A formed product made of the matrixcomprising chitosan and particles of cystine dispersed in said matrix;the said product is used for releasing a material selectively in a largeintestine part of a lower gastrointestional tract.